PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a common (prevalence 10?100%) and potentially dose-limiting side effect of many cancer chemotherapy drug treatment regimens. Clinically, CIPN presents with pain that is burning, shooting or electric-shock-like. The increase in prevalence of cancer coupled with an increase in the cancer survival rates due to chemotherapy regimens is transforming cancer pain into a large, unmet medical problem. Neurotoxic chemotherapeutic agents (e.g., antimicrotubule agents like paclitaxel) may cause structural damage to peripheral nerves, resulting in aberrant somatosensory processing in the peripheral and/or central nervous system. Dorsal root ganglia (DRG) sensory neurons as well as neuronal cells in the spinal cord are the preferential sites in which chemotherapy induced neurotoxicity occurs. Pathogenesis is complex but includes alterations in ion channels and ectopic activation of nociceptors. For example, paclitaxel- induced chemotherapy increases the excitability of DRG neurons with a commensurate increase in NaV1.7, a voltage-gated sodium channel. NaV1.7 is expressed in both large and small diameter DRG neurons and in most functionally identified nociceptors. Of the nine Na+ channel isoforms, NaV1.7 plays a key role in setting the threshold for action potential generation in primary sensory neurons. Genetic and functional studies have established NaV1.7 as a major contributor to pain signaling in humans. NaV1.7 has been difficult to target selectively over other voltage-gated sodium channels due to high sequence similarity between isoforms. Therefore, alternative approaches are still needed for developing drugs targeting NaV1.7. Regulonix LLC's approach has the potential to be a paradigm shift because we are targeting NaV1.7 indirectly by focusing on a signaling pathway that controls surface expression and activity of this channel. From the calcium channel pain therapeutics literature it is clear that no one drug is efficacious in relieving pain in all patients. Whether this also holds true for current NaV1.7 drugs is an open question. Thus, development of a `third' generation of NaV1.7 ?inhibitors?, such as the Regulators of NaV channels (i.e. ReNs) proposed here, is needed. Regulonix objectives in this STTR are to identify ReNs that exhibit more efficacious and safer profiles than current drugs for CIPN and that display extended durations of action. Doing so allows for a phase II STTR application for the IND-enabling studies of a selected ReN. Regulonix's specific aims are: (1) To elucidate channel specificity and biophysical properties of select ReNs to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells; (2) To validate the drug properties of optimized ReNs both in vitro and in vivo; and (3) to identify optimized ReNs for preclinical efficacy using a pain model (CIPN) and determine neurological side-effects (motor impairment, memory, weight gain, and smell) that provide information about efficacy and functional toxicity. At the conclusion of our study, we expect to have a validated ReN and worthy backup compounds.